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AKT-mTOR Signaling: The Key to Enhanced Tendon Differentiation of MSCs?

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Review of “Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells” from STEM CELLS by Stuart P. Atkinson

While engineered muscle and bone tend to hit the regenerative medicine headlines, the differentiation of mesenchymal stem cells (MSCs) into tendon-like tissues represents an important but perhaps unappreciated clinical aim. Tendons, mainly composed of collagen fibrils, connect muscle to bone and the endogenous repair of injury caused by overuse or age-related degeneration [1] represents an unfortunately slow and inefficient process. For these reasons, studies have sought to harness the tenogenic differentiation of MSCs for therapeutic purposes.

A recent STEM CELLS study from the laboratories of Yi Ting Zhou and Xiao Chen (Zhejiang University, PR China) aimed to develop new therapeutic approaches for tendon injury by understanding the signaling pathways involved in tendon production [2]. To this end, Cong et al. explored the relevance of AKT-mTOR signaling axis in tendon differentiation of MSCS, given the evidence that mTOR (mechanistic target of rapamycin) plays essential roles in bone and muscle production [3, 4]. Could this new study reveal the key to enhanced tenogenic differentiation of MSCs and improved tendon tissue repair?

This fascinating new study on the signaling pathways controlling tenogenic differentiation of MSCs established that:

 

  • Treatment with pro-tendon growth factors, such as TGF-β1 and IGF-1, or directed tenogenic differentiation (employing ascorbic acid containing differentiation media) associated with increased mTOR signaling in mouse MSCs 
  • Diseased human tendon tissues displayed diminished mTOR and AKT2 levels
    • Statin treatment, known to lower-lipid levels and induce tendinopathies or ruptures as a side-effect [5], also MSC tenogenesis due to inhibited AKT-mTOR signaling
  • Inhibition of AKT (using MK-2206 and AKT inhibitor IV) and mTOR (using rapamycin and PF-04691502) or depletion of AKT and mTOR via the expression of specific siRNAs prompted a reduction in the production of type I collagen and tenogenesis of MSCs
  • In vitro analysis discovered that mTOR inhibition in MSCs undergoing tenogenesis led to a significant decrease in collagen fibril diameter of tendon-like structures 
  • In vivo analyses employing a tendon-specific mTOR gene knockout mouse model discovered decreased limb grip strength and increased levels of tendon defects

 

These combined findings highlight the relative importance of the AKT-mTOR signaling axis in tenogenesis of MSCs and so may provide an important therapeutic target to improve current tendon repair strategies.

To keep up to date with all the new studies involving tenogenesis of MSCs and related therapeutic strategies, stay tuned to the Stem Cells Portal.

References

  1. Subramanian A and Schilling TF, Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix. Development 2015;142:4191-204.
  2. Cong XX, Rao XS, Lin JX, et al., Activation of AKT‐mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells. STEM CELLS 2018;36:527-539.
  3. Xian L, Wu X, Pang L, et al., Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 2012;18:1095-101.
  4. Ge Y and Chen J, Mammalian target of rapamycin (mTOR) signaling network in skeletal myogenesis. J Biol Chem 2012;287:43928-35.
  5. Marie I, Delafenêtre H, Massy N, et al., Tendinous disorders attributed to statins: A study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature. Arthritis Care & Research 2008;59:367-372.